Development of inhibitors of lactate transport as an anticancer strategy : chemical synthesis, in vitro functional screening and in vivo therapeutic validation

Proliferating cancer cells consume glucose at a high rate and release lactate. This adaptive metabolism provides tumor cells with ATP as an energy source but also with major anabolic intermediates. In addition, lactate can stimulate angiogenesis and when re-captured by oxidative cancer cells can feed the TCA cycle after reconversion into pyruvate. Monocarboxylate transporters (MCT)therefore represent potential therapeutic targets to limit tumor progression. Rational design and pharmacomodulation led us to identify 7-aminocarboxycoumarins (7ACC) as a scaffold endowed with inhibitory effects on lactate transport. We first compared the cytotoxic potential of our compounds in either glucose- or lactate-containing medium. This primary assay led us to identify hits that inhibited cell proliferation in lactate conditions but failed to exert toxic effects in the glucose condition. The secondary assay confirmed that our hits functionally block lactate influx. In a third assay based on the measurement of [14C]-lactate uptake in minute-range periods, we validated our hits as bona fide inhibitors of lactate influx through either MCT1 or MCT4. In vivo proof of principle of the antitumor effects of 7ACC, showing a favorable pharmacokinetic profile, was obtained in nude mice bearing human breast, cervix, bladder and colorectal cancers. 7ACC compounds consistently led to significant tumor growth delays except for bladder tumors in adequation with the lack of MCT1/4 expression in these tumors. Antitumor effects were further increased when 7ACC were combined with conventional chemotherapy or radiotherapy. Altogether, these results confirm the rationale to interfere with lactate transport in tumors and validate a new family of MCT inhibitors as an efficient anticancer strategy.